1. Field of the Invention
This invention relates to pterostilbene, an analog of resveratrol, found in grapes, wine, peanuts and other berries. Pterostilbene activates the peroxisome proliferator-activated receptor alpha (PPARα) isoform, a receptor proposed to mediate the activity of lipid-lowering drugs. As a PPARα agonist, pterostilbene is capable of acting as an effective hypolipidemic agent.
2. Description of the Relevant Art
The peroxisome proliferator-activated receptor (PPAR) isoforms are members of the nuclear receptor superfamily of ligand-activated transcription factors. They were first identified in Xenopus frogs as receptors that induce the proliferation of peroxisomes (Dreyer et al. 1992. Cell 68: 879-887). Three PPAR isoforms are known: PPARα, PPARγ, and PPARδ. The PPARs control gene expression by interaction with specific response elements in the promoter region of target genes (Tugwood at al. 1996. Ann. New York Acad. Sci. 804: 252-265). The PPARs play a central role in carbohydrate and lipid homeostasis, and govern other biological processes such as energy metabolism, cell proliferation and differentiation, and inflammation (Chakrabarti and Rajagopalan. 2004. Curr. Med. Chem.: Immunol. Endocr. Metab. Agents 4: 67-73; Escher and Wahli. 2000. Mutation Res. 448: 121-138; Gilde and Van Bilsen. 2003. Acta Physiol. Scand. 178: 425-434; Kersten, S. 2002. Eur. J. Pharmacol. 440: 223-234; Mudaliar and Henry. 2002. Curr. Opin. Endocrinol. Diabetes 9: 285-302). The PPARs are also suggested to play a role in the pathogenesis and proliferation of colorectal (Jackson et al. 2003. Gut 52: 1317-1322) and lung (Inoue et al. 2001. Anticancer Res. 21: 2471-2476) tumor progression possibly via inhibition of proliferation. The PPARα isoform, predominantly involved in fatty acid and lipid catabolism and import, activates genes involved in fatty acid oxidation in the liver, heart, kidney, and skeletal muscles (Fruchart et al. 2003. Prog. Exper. Cardiol. 8: 3-16; Gilde and Van Bilsen, supra). In the liver, activation of PPARα leads to increased β-oxidation of fatty acids and decreased triglyceride-VLDL synthesis (Fruchart and Duriez. 2004. Ann. Pharmaceut. Franc. 62: 3-18). Activation of PPARα also leads to the reduction of triglyceride because of repression of hepatic apolipoprotein C-III and to the increase in lipoprotein lipase gene expression (Gervois et al. 2000. Clin. Chem. Lab. Med. 38: 3-11). Furthermore, PPARα activation causes induction of hepatic apolipoprotein A-I and A-II expression, in humans, leading to increased plasma HDL cholesterol. PPARα agonists also slow down the progression of premature coronary atherosclerosis (Fruchart et al. 2003, supra) and have been demonstrated to regulate metabolism of amino acids in the liver (Kersten et al. 2001. FASEB J. 15: 1971-1978).
Resveratrol is a well-known antioxidant (Stivala et al. 2001. J. Biol. Chem. 276: 22586-22594; Teguo et al. 1998. J. Nat. Prod. 61: 655-657) and cancer chemopreventive compound (Jang et al. 1997. Science 275: 218-220) present in grapes and wine. Its occurrence in wine has been linked to low incidence of fatal coronary heart disease among populations consuming wine moderately (Hegsted and Aussman. 1988. J. Nutr. 118: 1184-1189; Renaud and De Lorgeril. 1992. Lancet 339:1523). Dietary resveratrol at 50 ppm suppressed the blood serum lipid peroxidase levels in rats, and dose-dependently suppressed serum triglyceride and very-low-density lipoprotein-(VLDL-) and low-density-lipoprotein-(LDL-) cholesterol levels (Miura et al. 2003. Life Sci. 73: 1393-1400).
Pterostilbene is another grape compound that also was found to have antioxidant (Rimando et al. 2002. J. Agric. Food Chem. 50: 3453-3457; Stivala et al., supra) and cancer chemopreventive property similar to resveratrol (Rimando et al., supra). Pterostilbene has antidiabetic (Manickam et al. 1997. J. Nat. Prod. 60: 609-610) properties, and inhibits the enzymes cyclooxygenase-1 (COX-1) and COX-2, inferring anti-inflammatory properties (Likhitwitayawuid et al. 2002. Planta Medica 68: 841-843). Furthermore, pterostilbene is cytotoxic to a number of cancer cell lines in vitro (Rimando et al. 1994. Nat. Prod. Lett. 4: 267-272).
Like resveratrol and pterostilbene, piceatannol, has a cancer chemopreventive property (Waffo-Teguo et al. 2001. Nutrition and Cancer 40: 173-179), and is a stronger antioxidant than resveratrol and a potent anti-arrhythmic agent (Hung et al. 2001. Free Radical Biol. Med. 30: 877-883; Lee et al. 1998. Combinat. Chem. High Throughput Screen 1: 35-46). The cytochrome P450 enzyme CYP1B1 metabolizes resveratrol to piceatannol, demonstrating that a natural cancer chemopreventive agent can be converted to an anticancer compound by an enzyme which is over expressed in a wide variety of human tumors (Potter et al. 2002. Brit. J. Cancer 86: 774-778). Piceatannol showed anti-allergic effects in experimental models of type I allergy (Matsuda et al. 2001. Biol. Pharm. Bull. 24: 264-267). It has also been shown to induce apoptotic cell death in BJAB lymphoma cells with activity equal to resveratrol. Piceatannol also induced apoptosis in ex vivo assays with leukemic lymphoblasts, whereas resveratrol did not (Wieder et al. 2001. Leukemia 15: 1735-1742). Resveratrol trimethylether was found to be more cytotoxic than resveratrol in cultured human lung and colon cancer cells (Lee et al. 2003. Arch. Pharm. Res. 26: 253-257).
Thus, in view of reports on the hypolipidemic property of resveratrol, the three analogs were of interest because their biological activity profiles are similar to that of resveratrol and in some assays are reported to be more potent than resveratrol. The goal of this work was to investigate whether these analogs are PPARα activators.